Project Summary Plasmodium vivax is a major cause of clinical malaria in many parts of Southeast Asia and Latin America and causes substantial morbidity and economic loss in the developing world. P. vivax mainly invades young red blood cells and is highly dependent on the human Duffy antigen receptor for chemokines (DARC) protein for invasion. Individuals lacking DARC are highly resistant to invasion, and those having half the amount of Duffy protein on the erythrocyte surface have lower parasitemia infections, indicating this interaction may be very sensitive to vaccine interventions. P. vivax binds to DARC through the Duffy binding protein region II (PvDBPII). Antibodies to PvDBPII inhibit parasite invasion and are correlated with protective immunity, but the main obstacle to vaccine development is generating high titer functional antibodies that will prevent disease. The three dimensional structure has been solved for a homolog of PvDBPII and critical binding residues have been identified. This project will use rational structure-based immunogen modifications in combination with protein multimerization to enhance the immunogenicity of PvDBPII to elicit high titer functional antibodies that block P. vivax invasion and facilitate vaccine efficacy.